HIP/RPL29 antagonizes VEGF and FGF2 stimulated angiogenesis by interfering with HS-dependent responses

Sonia D'Souza, Weidong Yang, Dario Marchetti, Caroline Muir, Mary C. Farach-Carson, Daniel D. Carson

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

HIP/RPL29 is a heparan sulfate (HS) binding protein with diverse activities including modulation of heparanase (HPSE) activity. We examined HIP/RPL29's ability to modulate actions of HS-binding growth factors (HBGFs) in angiogenesis. Between 1 and 2.5 g/ml (ca. 60-150 nM), HIP/RPL29 inhibited HBGF-stimulated endothelial cell tube formation. Aortic explant outgrowth also was inhibited, but at higher concentrations (40 g/ml). At this concentration, HIP/RPL29 had no effect on HBGF-stimulated MAPK phosphorylation or VEGF-stimulated receptor-2 phosphorylation at site Y-996. Partial inhibition occurred at VEGF receptor-2 site Y951, associated with cell migration. HBGF displacement from HS-bearing perlecan domain I showed that HIP/RPL29 released 50% of bound HBGF at 20 g/ml, a dose where endothelial tube formation is inhibited. Similar FGF2 release occurred at pH 5.0 and 7.0, conditions where HPSE is highly and residually active, respectively. We considered that HIP/RPL29 inhibits HPSE-dependent release of HS-bound HBGFs. At pH 5.0, release of soluble HS was inhibited by 64% at concentrations of 5 g/ml and by 77% at 40 g/ml, indicating that HIP/RPL29 antagonizes HPSE activity. At concentrations up to 40 g/ml (ca. 2.5 M) where angiogenic processes are inhibited, release of FGF2 occurred in the presence of HPSE and HIP/RPL29. The majority of this FGF2 is not bound to soluble HS. Studies of HIP/RPL29 binding to HS indicated that many structural features of HS are important in modulation of HBGF activities. Our findings suggest that inhibition of angiogenic processes by HIP/RPL29 involves attenuation of the formation of soluble, biologically active HBGF:HS complexes that activate HBGF receptors.

Original languageEnglish (US)
Pages (from-to)1183-1193
Number of pages11
JournalJournal of Cellular Biochemistry
Volume105
Issue number5
DOIs
StatePublished - Dec 1 2008

Keywords

  • FGF2
  • HIP/RPL29
  • Heparan sulfate
  • Heparanase
  • VEGF

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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